1. Field of the Invention
This invention relates to certain compounds having antagonistic activity towards the neuropeptides cholecystokinin (hereinafter CCK) and gastrin.
CCK and gastrin are peptides, endogenous in human and other species, which regulate biological functions in tissues in the GI tract and central nervous systems (CNS). Gastrin and CCK regulate biological activity by acting as autocrine, parocrine, endocrine or neuromodulatory agents.
The first and principal form of gastrin isolated was the 17 amino acid residue peptide, G-17 or little gastrin. The second major molecular form of gastrin is the 34 amino acid residue peptide, G-34 or big gastrin. G-34 is considered the proform of G-17, but both forms of gastrin are biologically active and nearly equipotent. The smallest residue possessing biological activity is G-4 which is the final 4 amino acids at the carboxyl terminal. Sulfation of the tyrosine residue (6-amino acids from the C-terminal) is not necessary for expression of the bioactivity of gastrins.
The major physiologic action of gastrin is the stimulation of acid secretion from the stomach. Gastrin stimulates acid secretion by at least three separate actions: direct stimulation of parietal cell activity; potentiating interaction with histamine, a paracrine stimulus; and, quantitatively, by release of histamine.
Gastrin is a trophic hormone for gastric, fundic and intestinal mucosa and for the pancreas. Gastrin directly stimulates those biochemical processes, DNA and RNA synthesis, that are involved in tissue growth.
Gastrin also stimulates pepsin secretion and increases gastric mucosal blood flow. It causes electrolyte and water secretion by the stomach, pancreas, liver, and Brunner's glands.
Other possible actions of gastrin may involve the regulation of lower esophageal sphincter contraction and other smooth muscle contractions (motility) in the GI tract.
CCK is a linear amino acid polypeptide that occurs in several bioactive molecular forms: CCK-8, CCK-22, CCK-33, CCK-39 and CCK-58 are the major forms which have been reported. All of the CCK variants require the sulfation of the tyrosine residue at position 7, counting from the C-terminal, for the full expression of their biologic activity.
The principal physiologic actions of CCK are stimulation of contraction of gallbladder and of pancreatic enzyme secretion. There is evidence which supports a physiologic role of CCK in the inhibition of gastric emptying, stimulation of pancreatic growth and release of pancreatic polypeptide.
Other possible actions of CCK include stimulation of insulin, glucagon, somatostatin and peptide YY release, stimulation of hepatic bile flow, intestinal motility, blood flow in the superior mesenteric artery, secretion of pepsinogen from gastric glands, and secretion of bicarbonate from the stomach and duodenum. In contrast to gastrin, CCK relaxes the lower esophageal sphincter.
In the nervous system CCK may act as a neurotransmitter or as a neuromodulator. As such, exogeneous CCK has been shown to effect memory. Also levels of acetylcholine and dopamine have been effected by exogenoeus CCK. CCK has been implicated as well for producing the satiety effect, however, it is not clear if this is regulated by peripheral or central mechanisms.
There is considerable overlap in the biological activities elicited by gastrin and CCK. Therefore, antagonists for gastrin or CCK may also possess activities at the CCK or gastrin receptors.
2. Reported Developments
Four distinct chemical classes of CCK-A (peripheral CCK) receptor antagonists have been reported (see R. M. Freidinger, Medicinal Research Reviews, Vol. 9, No. 3, 271-290 (1989)).
(1) Cyclic nucleotides eg. dibutyryl cyclic GMP (see N. Boilos et al., Am. J. Physiol. 242, G 161 (1982) and P. Robberecht et al., Mol. Pharmacol., 17, 268 (1982).
(2) Amino acid derivatives, characterized by proglumide, a derivation of glutaramic acid and N-acylated tryptophans, i.e. para-chlorobenzoyl-L-tryptophan (benzotrypt) (see W. F. Hohne et al., Proc. Natl. Acad. Sci. USA, 87, 6304 (1981) and R. T. Jensen et al., Biochem. Biophys. Acta. 761, 269 (1983); also second generation proglumide analogues typified by Lorglumide and Loxiglumide (F. Makovec et al., Arzneim-Forsch., 37(II), 1265 (1987)). The latter two analogues have considerably better receptor affinity and selectivity.
(3) Peptide and pseudopeptide analogs based on the C-terminal end of CCK, especially analogues of CCK-8, Asp-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-Phe-NH.sub.2. Some examples are Cbz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2 (M. Spanarkel et al., J. Biol. Chem. 258, 6746 (1983)) and Boc-Tyr(SO.sub.3 H)-Met-Gly-D-Trp-Nle-Asp-OCH.sub.2 CH.sub.2 Ph (M. F. Lignon et al. J. Biol. Chem. 262, 7226 (1987)).
(4) Non-peptide structures--the fermentation product, asperlicin (R. S. L. Chang et al., Science 230, 177 (1985)) and subsequent medicinal chemistry done on this compound which culminated in the very high CCK-A affinity 1,4-benzodiazepine (MK329) series (B. E. Evans et al., J. Med. Chem. 31, 2235-2246, 1988).
Structurally related compounds which retain nanomolar level potency for CCK have recently been reported, e.g. 3-aminobenzolactam (R. S. L. Chang and W. H. Parsons, Eur. Pat. Appl. EP 166,345, 1986, and W. H. Parsons et al., J. Med. Chem., 32, 1681-1685, 1989) and .beta.-carbolines (B. E. Evans, Eur. Pat. Appl. EP 304233, 1988 and M. Itonaga et
al , Japan. J. Pharmacol., 46, 319-324, 1988).
Compounds selective for the peripheral gastrin receptor also possess strong affinity for the CCK-B receptor (a CCK receptor located in CNS). Presently there are no known agents which differentiate between the CCK-B receptor and the peripheral gastrin receptor. Compounds selective for gastrin generally fall into two major classes.
(1) Peptide and pseudopeptide analogs based on C-terminal amino acids of CCK or gastrin, especially CCK-4 (Phe-Met-Asp-Phe-NH.sub.2). Some examples are the pseudopeptide Boc-Trp-Leu-.PSI.(CH.sub.2 NH)-Asp-Phe-NH.sub.2 in which the peptide bond between leucine and aspartic acid has been replaced by CH.sub.2 NH bond and has the same binding affinity as Boc-Trp-Leu-Asp-Phe-NH.sub.2 but has no agonist activity (J. Martinez et al., J. Med. Chem., 28, 1874, 1985).
Other analogues of CCK-4 containing partial retroinverso modifications have been demonstrated to bind strongly to the gastrin receptor and block the effects of gastrin in the rat (in vivo) eg. Boc-Trp-Leu-gAsp-m(R,S)Phe-NH.sub.2 (M. Rodriguez et al., J. Med. Chem., 30, 758-763, 1987).
Recently some cyclic cholecystokinin analogues of CCK-8 (Asp-Tyr(SO.sub.3 H)-Met-Gly Trp-Met-Asp-Phe-NH.sub.2) eg. ##STR2## (where Ahx=2-aminohexanoic acid) have demonstrated selectivity for the CCK-B (CNS) receptor relative to CCK-A - (peripheral). (B. Charpentier, et al., Proc. Natl. Acad. Sci. USA, 85, 1968-1972, 1988.)
(2) Benzodiazepines - the 3-substituted 1,4-benzodiazepines effective as selective antagonists of CCK-A have been modified synthetically resulting in agents selective for the peripherial gastrin and CCK-B (brain) receptors, such as the Merck compound L-365,260 (V. J. Lotte and R. S. L. Chang, Env. J. of Pharm., 162, 273-280, 1989, also M. G. Bock et al., J. Med. Chem., 32, 16-23, 1989).
Other non-peptide, non-benzodiozepine compounds have been reported (eg. analogs of Virginiamycin M1) to display strong binding affinity selectively for gastrin (relative to CCK-A pancreas) (Y.-K. T. Lam et al., U.S. Pat. No. 4,762,923 (1988)).
Heretofore tetrahydro-pyrido-indoles have not been reported to possess cholecystokinin and/or gastrin antagonists activities.